This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of effective medications to treat cocaine addiction will depend on a better understanding of cocaine neuropharmacology. The current project utilized positron emission tomography (PET) neuroimaging techniques in nonhuman primates as a noninvasive approach to investigate cocaine-induced functional changes in central nervous system activity. The major emphasis has been on the effects of monoamine transporter inhibitors on cocaine self-administration and dopamine neurochemistry. Our current goal is to define the optimal level of serotonin transporter occupancy in suppressing cocaine use. We have also completed a long series of studies to characterize the neuropharmacology of 3,4-methylenedioxymethamphetamine (MDMA), an abused amphetamine-type stimulant. Overall, the results support our hypothesis that the enantiomers of MDMA have a distinct pharmacology with selective dopaminergic and serotonergic effects. This may explain the unique pharmacology of racemic MDMA in humans. We have also made significant progress in the development of fMRI in awake monkeys in order to characterize cocaine- and cue-induced brain activation at a neurocircuitry level. We have recently implemented an eye-tracker system that allows for the documentation of visual contact with displayed items during the acquisition of blood oxygenation level dependent (BOLD) fMRI. We are using this system to define the neurocircuitry that is engaged as the rhesus monkeys are exposed to visual cues associated with cocaine self-administration. Collectively, the results have important implication concerning the development of substitute agonist pharmacotherapies to treat stimulant abuse.